Phosphodiesterase (PDE) catalyzes the hydrolysis of cyclic nucleotides cGMP and cAMP, and thereby regulates various physiological responses by controlling the intracellular concentrations of these two important secondary signaling factors. Abnormal regulation of the cyclic nucleotides cGMP and cAMP molecules is the cause of many diseases. There are a number of drugs ameliorating and treating diseases by inhibiting PDE activity, for example, PDE5 inhibitor used for pulmonary hypertension, and PDE4 inhibitor used for arthritis caused by psoriasis. Currently, the known phosphodiesterase genes can be classified into eleven major categories, each of which can be expressed into several subtypes, with a total of more than 100 PDE subtypes. Different subtypes have different structures and different tissue distributions, and have great differences in the activities against the cyclic nucleotides cGMP and cAMP, so that they can regulate various physiological functions.
PDE2 phosphodiesterase can catalyze the hydrolysis of cyclic nucleotides cGMP and cAMP, in the meantime, the activity of cAMP is regulated by cGMP, which plays a critical role in balancing the functions of cGMP and cAMP in cells. PDE2 is widely expressed in human tissues, mainly distributed in heart, central nervous system, liver, adrenal gland, endothelial cells, platelets, and etc. PDE2 is involved in regulating various physiological activities, such as central learning, memory, cognition and other processes, maintaining the basic rhythm of heart, smooth muscles and endothelial cells, the permeability of endothelial cells, and regulating inflammatory response. PDE2 gene-knockout mice directly lead to embryonic death. Inhibition of PDE2 activity might be applied to various central and cardiovascular diseases, and to controlling the inflammatory response.
It was found long time ago that a variety of natural and synthetic purine compounds, such as caffeine, theophylline, pentoxifylline and the like, have non-selective PDE inhibitory activity. Pentoxifylline (with PDE2 activity) has been clinically approved for use in the treatment of lower limb claudication caused by obstruction of the peripheral blood vessels, and its primary roles are to reduce blood viscosity, improve erythrocyte deformation, inhibit platelet aggregation and etc. It has also been reported that some novel high selective PDE2 inhibitors can be used for controlling endothelial cell division and revascularization, and improving central cognitive disorder. In generally, however, the development and application of the novel PDE2 inhibitors is still very limited, and the discovery and application of the novel PDE2 inhibitors has broad prospects.
Tumor necrosis factor α (TNF-α) is a kind of cytokines with multiple biological activities, has important influence on the occurrence, development and prognosis of various diseases. TNF-α is mainly produced by monocytes and macrophages, involved in the immune regulation and cytokine network coordination. Under normal circumstances, TNF-α plays an important role in immune defense and immune surveillance, but in some cases it has a negative effect. Studies have shown that TNF-α overexpression can induce the expression of proinflammatory cytokines such as interleukin-1 (IL-1), IL-6 and the like, improve the permeability of endothelial cells, up-regulate the expression of adhesion molecules, activate neutrophils and eosinophils, as well as induce bone synovial cells and chondrocytes to secrete acute phase substances, tissue degrading enzymes and the like so as to promote the occurrence of inflammation. These pathological responses play a very important role in the development of many immune-mediated inflammatory diseases (IMID), such as rheumatic arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), inflammatory bowel disease (IBD), juvenile chronic arthritis (JCA), vasculitis and the like. Some studies have shown that TNF-α is an ideal target for multiple IMIDs mentioned above, and the use of TNF-α inhibitors to neutralize excess TNF-αt is an ideal way to prevent and treat chronic inflammatory diseases caused by TNF-α overexpression. PDE2 can regulate the expression of TNF-α in the theory of mechanism. Thus, the TNF-α level of can be controlled by regulating PDE2 activity, and therefore the inflammatory response can be controlled.